1. Field of the Invention
The present invention relates generally to biocompatible polymeric compositions and methods for their production and use. More particularly, the present invention relates to compositions for promoting hemostasis and delivery of bioactive substances.
The ability to inhibit bleeding in a patient (hemostasis) and deliver bioactive substances to the patient (drug delivery) are both of great medical importance. Over the years numerous devices, compositions, and biological agents have been developed for both purposes. As no one device, composition, or approach can fulfill all medical needs, there continues to be a need to provide alternative and improved modalities for achieving both hemostasis and drug delivery.
In particular, it would be desirable to provide new and alternative compositions which are suitable for performing either or both hemostasis and drug delivery to patients. Preferably, such compositions should be a convenient matrix for topical delivery to surgical and/or traumatic wounds to a patient""s tissue structures or skin. In particular, such compositions should be dry, be capable of storage for prolonged periods, be in a sheet or other easily manipulable form to facilitate placement, require minimum preparation by a user prior to use, be relatively easy to fabricate, be compatible with the delivery of a wide variety of biological and other active agents, and the like. In the case of hemostatic materials, it would be particularly advantageous to be able to remove excess material without causing further bleeding or other adverse events. At least some of these objectives will be meet by the embodiments of the invention described hereinafter.
2. Description of the Background Art
Biodegradable injectable drug delivery polymers are described in U.S. Pat. No. 5,384,333 and by Jeong et al. (1997) xe2x80x9cNature,xe2x80x9d 388:860-862. Biodegradable hydrogels for controlled released drug delivery are described in U.S. Pat. No. 4,925,677. Resorbable collagen-based drug delivery systems are described in U.S. Pat. Nos. 4,347,234 and 4,291,013. Aminopolysaccharide-based biocompatible films for drug delivery are described in U.S. Pat. Nos. 5,300,494 and 4,946,870. Water soluble carriers for the delivery of taxol are described in U.S. Pat. No. 5,648,506.
Polymers have been used as carriers of therapeutic agents to effect a localized and sustained release (Langer, et al., Rev. Macro. Chem. Phys., C23(1), 61, 1983; Controlled Drug Delivery, Vol. I and II, Bruck, S. D., (ed.), CRC Press, Boca Raton, Fla., 1983; Leong et al., Adv. Drug Delivery Review, 1:199, 1987). These therapeutic agent delivery systems simulate infusion and offer the potential of enhanced therapeutic efficacy and reduced systemic toxicity.
Other classes of synthetic polymers which have been proposed for controlled release drug delivery include polyesters (Pitt, et al., in Controlled Release of Bioactive Materials, R. Baker, Ed., Academic Press, New York, 1980); polyamides (Sidman, et al., Journal of Membrane Science, 7:227, 1979); polyurethanes (Maser, et al., Journal of Polymer Science, Polymer Symposium, 66:259, 1979); polyorthoesters (Heller, et al., Polymer Engineering Scient, 21:727, 1981); and polyanhydrides (Leong, et al., Biomaterials, 7:364, 1986). U.S. Pat. No. 5,595,735 describes a thrombin paste composition using polyethylene glycols as carriers.
Collagen-containing compositions which have been mechanically disrupted to alter their physical properties are described in U.S. Pat. Nos. 5,428,024; 5,352,715; and 5,204,382. These patents generally relate to fibrillar and insoluble collagens. An injectable collagen composition is described in U.S. Pat. No. 4,803,075. An injectable bone/cartilage composition is described in U.S. Pat. No. 5,516,532. A collagen-based delivery matrix comprising dry particles in the size range from 5 xcexcm to 850 xcexcm which may be suspended in water and which has a particular surface charge density is described in WO 96/39159. A collagen preparation having a particle size from 1 xcexcm to 50 xcexcm useful as an aerosol spray to form a wound dressing is described in U.S. Pat. No. 5,196,185. Other patents describing collagen compositions include U.S. Pat. Nos. 5,672,336 and 5,356,614.
A polymeric, non-erodible hydrogel that may be cross-linked and injected via a syringe is described in WO 96/06883.
The following pending applications, assigned to the assignee of the present application, contain related subject matter: U.S. Ser. No. 09/032,370, filed on Feb. 27, 1998; U.S. Ser. No. 08/903,674, filed on Jul. 31, 1997; U.S. Ser. No. 60/050,437, filed on Jun. 18, 1997; U.S. Ser. No. 08/704,852, filed on Aug. 27, 1996; U.S. Ser. No. 08/673,710, filed Jun. 19, 1996; U.S. Ser. No. 60/011,898, filed Feb. 20, 1996; U.S. Ser. No. 60/006,321, filed on Nov. 7, 1996; U.S. Ser. No. 60/006,322, filed on Nov. 7, 1996; U.S. Ser. No. 60/006,324, filed on Nov. 7, 1996; and U.S. Ser. No. 08/481,712, filed on Jun. 7, 1995. The full disclosures of each of these applications is incorporated herein by reference. WO 98/08550, which claims priority from U.S. Ser. No. 08/903,674, described cross-linked biological polymers which are useful as a component of the materials of the present invention.
According to the present invention, hemoactive materials comprise a dried, cross-linked biologically compatible polymer which forms a hydrogel when exposed to blood and a non-cross-linked biologically compatible polymer which solubilizes when exposed to blood. A cross-linked polymer is dispersed in a dried matrix of the non-cross-linked polymer, and the materials are delivered to surgical sites, wounds, and other target regions in tissue which are subject to bleeding or otherwise have blood present. By xe2x80x9chemoactive,xe2x80x9d it is meant that the compositions will interact in some way with blood when exposed to blood. At a minimum, the non-cross-linked biocompatible polymer will solubilize in the presence of blood and release the cross-linked biologically compatible polymer so that it can hydrate and form a gel as it absorbs water from the blood. Thus, the non-cross-linked biologically compatible polymer forms a binder which maintains the cross-linked polymer in a desirable form prior to use. Usually, the compositions will be in the form of a sheet, typically having a thickness in the range from 1 mm to 25 mm, preferably from 2 mm to 15 mm. Alternatively, the materials can be formed into powders, pellets, large blocks, plugs, cylinders, tubes, split tubes, or other forms which may be conveniently delivered or placed to target tissue sites. Additionally, the xe2x80x9chemoactivexe2x80x9d materials may include other bioactive agents capable of providing desirable bioactivities. Of particular interest, the hemoactive materials may include hemostatic agents, such as blood clotting agents, e.g., thrombin, which will promote hemostatic activity of the material. A wide variety of other bioactive agents may be delivered, including other proteins, carbohydrates, nucleic acids, inorganic and organic biologically active molecules such as enzymes, enzyme inhibitors, antibiotics, anti-neoplastic agents, bacteriostatic agents, bactericidal agents, antiviral agents, anesthetics, anti-inflammatory agents, hormones, anti-angiogenic agents, antibodies, neurotransmitters, and the like. Additional components may be provided in the compositions, such as buffering agents, antioxidants, preservatives, viscosity modifiers, solubility modifiers, and the like, in order to enhance or modify the properties or shelf-life of the material. Preferably, the materials will be sterilized and maintained in a sterile package. Conventional sterilization methods include xcex3-irradiation, exposure to ethylene oxide, electronic beam irradiation, aseptic processing, and the like.
The compositions of the present invention will preferably comprise cross-linked biologically compatible polymers which are relatively persistent, usually having a degradation time of at least 1 day, preferably having a degradation time in the range from 2 days to 60 days. Conversely, the non-cross-linked biologically compatible polymers which form the binder will have a very short life and will typically dissolve in blood or aqueous media at physiologic temperature (37xc2x0 C.) in less than 15 minutes, preferably in from 30 seconds to 10 minutes. Preferred cross-linked polymers will be fragmented, i.e., be present in the materials as discrete dry particles which, upon subsequent hydration, will have a size in the range from 0.01 mm to 5 mm, preferably from 0.05 mm to 1 mm. The cross-linked polymers will be swellable, and will have an equilibrium swell when fully hydrated in the range from 200% to 5,000%, preferably from 500% to 1000%.
Equilibrium swell, expressed as a percentage, is defined as the ratio of the difference between the equilibrium wet weight and dry weight of the cross-linked polymer and the dry weight of the polymer as follows:       Equilibrium    ⁢          xe2x80x83        ⁢    Swell    ⁢          xe2x80x83        ⁢          (      %      )        =                              Wet          ⁢                      xe2x80x83                    ⁢          Weight                -                  Dry          ⁢                      xe2x80x83                    ⁢          Weight                            Dry        ⁢                  xe2x80x83                ⁢        Weight              xc3x97    100  
The equilibrium wet weight is measured after the polymer has had an extended period of time in contact with the wetting agent after which the polymer can no longer take up significant additional wetting agent. For example, a cross-linked polymer that takes up five times its dry weight in water at equilibrium is said to have an equilibrium swell of 500% in water. A cross-linked polymer that takes up no water (that is, its equilibrium wet weight is the same as its dry weight) is said to have an equilibrium swell of 0% in water.
The cross-linked polymer will usually be the predominant component of the material, typically being present at from 50 weight % to 95 weight % of the total weight of the material, preferably being present from 80 weight % to 95 weight % of the total weight of the material. The binder, in contrast will usually form a much smaller portion of the material, typically being present at from 50 weight % to 1 weight % of the total weight of material, usually being present at from 20 weight % to 1 weight %. Usually, a plasticizer will also be provided in the material, usually within the non-cross-linked phase of the material, and typically being present at from 1 weight % to 20 weight % of the total weight of the material, usually being present at from 3 weight % to 15 weight % of the material. Optionally, the plasticizer may be present in both the non-cross-linked polymer and the cross-linked polymer. Preferred plasticizers include polyethylene glycol, sorbitol, and glycerol.
The polymer which is cross-linked may be a protein, carbohydrate, non-biologic hydrogel-forming polymer or copolymer, or other biologically compatible polymer or combination of polymers which can form a hydrogel. Preferred polymers include proteins, such as gelatin, collagen, albumin, hemoglobin, fibrinogen, fibrin, fibronectin, elastin, keratin, laminin, casein, and the like. Preferred carbohydrate and carbohydrate derivative polymers include glycosaminoglycans, starches, celluloses, hemicelluloses, xylan, agarose, alginate, chitosan, and the like. Exemplary non-biologic hydrogel-forming polymers and copolymers include polyacrylates, polymethacrylates, polyacrylamides, polyvinyl polymers, polylactides-glycolides, polycaprolactones, polyoxyethylenes, and copolymers thereof. Usually, the degree of cross-linking of the cross-linked polymer will be selected to provide a desired swellability within the range set forth above.
The non-cross-linked biologically compatible polymer will usually be a protein or a carbohydrate and may be the same polymer as the polymer which is cross-linked. Exemplary proteins include gelatin, collagen, elastin, albumin, keratin, and the like. Exemplary carbohydrates include glycosaminoglycans, alginate, starch, cellulose, derivatives thereof, and the like. The non-cross-linked polymer may also be non-biological water soluble polymer, such as any of the hydrogel-forming polymers and co-polymers set forth above. A particularly preferred and exemplary hemoactive material according to the present invention comprises a dry matrix of non-cross-linked gelatin polymer and dry cross-linked gelatin polymer present as particles dispersed in the dry gelatin matrix. Such compositions are described in greater detail in the Experimental section hereinafter.
When delivering an active agent, the active agent may be present in either the non-cross-linked polymer or the cross-linked polymer, or both. When present only in the non-cross-linked polymer, the active agent will be released substantially immediately when the material first dissolves upon contact with blood. When present in the non-cross-linked polymer, the material will be released much more gradually, typically over the entire time in which the cross-linked polymer degrades. Optionally, the same or different active agents can be provided in the two different phases of the material in order to provide different controlled release rates of the bioactive agent(s).
The materials of the present invention may be formed as sheets, powders, pellets, plugs, tubes, split tubes, cylinders, or the like, as generally described above. Such forms of the material are preferably produced sterilely (e.g., by aseptic processing) or sterilized and provided in sterile packs as part of kits. In addition to the sterile packs containing the solid forms of the materials, the kits will usually also contain instructions for use setting forth methods for inhibiting bleeding or delivering drugs by placing the sterilized materials at a target site in tissue, e.g., a wound or other site of bleeding tissue.
As a further aspect of the present invention, hemoactive materials may be made by dissolving a non-cross-linked biologically compatible polymer of the types described above in an aqueous medium. Particles of cross-linked biologically compatible polymer as described above are then suspended in the aqueous medium. The aqueous medium is then dried to form a solid phase comprising the dried polymeric particles in a dry matrix of the non-cross-linked polymer. Lyophilization (freeze-drying) is the preferred drying technique, although air drying, heat-assisted drying, spray drying, molding, and other methods could also be used under certain circumstances.